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Bland cholestasis characterized by extensive canalicular bile plugs, which are present mostly around the central venules and are not accompanied by inflammation or necrosis, can be caused by many drugs. H&E × 40
Source publication
Purpose of Review
Drug-induced liver injury (DILI) may be caused by prescription or over-the-counter medications, herbals and nutritional supplements, or environmental agents. This review provides an overview of (1) pathogenetic mechanisms and risk factors, (2) biochemical classification, (3) diagnostic approach, (4) role of liver biopsy, and (5) n...
Citations
... DILI diagnosis is primarily based on exclusion criteria, ruling out other potential causes of liver injury. It is crucial to recognize that approximately 10% of individuals experiencing hepatocellular jaundice attributed to drug use may progress to liver failure, making the prompt identification and monitoring of DILI cases essential for patient safety [80]. Therefore, more research is needed to develop reliable biomarkers and diagnostic tools to improve DILI's early detection and management, ultimately enhancing patient outcomes. ...
... These findings underscore the relevance of in silico simulations in assessing the liver safety profile of drugs across diverse patient populations [77,78]. The regulatory definition of a "Hy's Law Case" involves specific criteria, including ALT levels greater than three times the ULN and total bilirubin levels greater than two times the ULN, along with evidence of hepatocellular injury (R values > 0.5), drug-induced ALT elevations exceeding three times the ULN (known as "Temple's Corollary"), and the absence of other more likely causes for the injury [80]. Risk management strategies for DILI are generally ineffective, and mild elevations in ALT may not always reflect liver injury but could be attributed to other factors, such as muscle-related issues. ...
... Individuals with pre-existing liver conditions like NAFLD may have reduced liver function and impaired drug metabolism, increasing their vulnerability to DILI. Similarly, individuals with TD2 may experience altered drug metabolism due to insulin resistance [86] and changes in liver enzyme activity, further elevating the risk of DILI [79,80]. The eDISH plots suggested an increased risk in T2D and NAFLD patients, prompting the importance of vigilance in these patients [80]. ...
Lamotrigine, widely used for managing epilepsy and bipolar disorder, carries potential side effects, including severe anticonvulsant hypersensitivity syndrome (AHS) or drug rash with eosinophilia and systemic symptoms (DRESS), which may lead to hepatotoxicity. Patients with Type 2 Diabetes (TD2) and Non-Alcoholic Fatty Liver Disease (NAFLD) are identified as more susceptible to these adverse reactions. This exploratory analysis aims to identify clinical parameters influencing lamotrigine pharmacokinetics across diverse populations, shedding light on toxicity and therapeutic drug monitoring (TDM) considerations. Starting with a retrospective analysis of 41 lamotrigine-treated patients at Hospital Santo António reveals changes or deviations from normal levels in various blood parameters and significant correlations between these parameters. Serum level changes, including creatinine, albumin, gamma-glutamyl transferase, total bilirubin, and Vitamin B12, are observed, with strong negative correlations between Vitamin B12 and creatinine. Then, we used GastroPlus and DILIsym to explore the impact of clinical parameters on lamotrigine for different patient populations. We constructed a Physiologically Based Pharmacokinetic (PBPK) model for lamotrigine in GastroPlus, based on ADMET predictions and data from the literature, to simulate the pharmacokinetic variability of lamotrigine in different populations, and we visualized the impact of increasing lamotrigine dose on its plasma concentration–time profiles (200 mg, 400 mg, 600 mg, 1200 mg) and reduced bioavailability. At higher doses, it is possible that the saturation of metabolic pathways leads to the formation of toxic metabolites or intermediates. These metabolites may exert inhibitory effects on drug-metabolizing enzymes or disrupt normal physiological processes, thereby impeding the drug’s clearance and potentially lowering its bioavailability. In DILIsym, we investigated lamotrigine’s DILI potential for individuals with diabetes and NAFLD. The results demonstrated an increased risk, emphasizing the need for careful monitoring. This study underscores the importance of understanding lamotrigine’s pharmacokinetics for tailored treatment decisions, improved outcomes, and minimized adverse reactions.
... The highly active metabolic machinery, as well as the low content of anti-oxidant defense system in the heart exaggerates the DOX-associated cardiotoxicity [15]. Similarly, DOX-induced hepatotoxicity (DIH) is an ideal example of drug-induced liver injury (DILI) [16]; DIH could be enhanced by an acute single dose of DOX that is capable of provoking irreversible hepatic damage and triggering apoptosis and oxidative stress through decreasing the hepatic activity to detoxify ROS [17,18]. ...
Doxorubicin (DOX) is one of the widely used anti-tumor drugs. However, DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) are among the side effects that limited its therapeutic efficiency and clinical applicability. This study aimed to investigate the cardioprotective and hepatoprotective potentials of curcumin (CMN)—a bioactive polyphenolic compound—in alleviating DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) in male rats. A single intraperitoneal (i.p.) dose of DOX (20 mg/kg) was used to induce DIC and DIH. DOX-intoxicated rats were co-treated with CMN (100 mg/kg, oral) for 10 days before and 5 days after a single dose of DOX. We studied the anti-inflammatory and anti-oxidative activities of CMN on biochemical and immunohistochemical aspects. DOX disrupted cardiac and hepatic functions and stimulated oxidative stress and inflammation in both tissues that was confirmed biochemically and immunohistochemically. DOX enhanced inflammatory interferon-gamma (IFN-γ) and upregulated immunoexpression of nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-alpha (TNF-α). DOX induced structural alterations in both cardiac and hepatic tissues. CMN demonstrated cardioprotective potential through reducing cardiac troponin I (cTn1) and aspartate amino transaminase (AST). In addition, CMN significantly ameliorated liver function through decreasing alanine amino transaminase (ALT) and, gamma-glutamyl transferase (GGT), total cholesterol (TC), and triglycerides (TG). CMN demonstrated anti-inflammatory potential through decreasing IFN-γ levels and immunoexpression of iNOS, NF-κB, and TNF-α. Histopathologically, CMN restored DOX-associated cardiac and liver structural alterations. CMN showed anti-oxidative and anti-inflammatory potentials in both the cardiac and hepatic tissues. In addition, cTn1, IFN-γ, and AST could be used as blood-based biomarkers.
... Pulmonary fibrosis (PF) is a chronic and progressive pathological condition with increased incidence that is characterized by lung remodeling and respiratory dysfunction due to uncontrolled deposition of collagen and extracellular matrix (ECM) [5]. Similarly, exposure to drugs and adverse drug reaction might result in drug-induced liver injury (DILI) which is regarded as a significant cause of hepatotoxicity worldwide with elevated incidence in recent years [6]; in addition, there is no specific clinical, biochemical, or histological feature for the diagnosis of DILI [7]. ...
Amiodarone (AMD) is a widely used antiarrhythmic drug prescribed to treat cardiac tachyarrhythmias; however, AMD has been reported to provoke pulmonary fibrosis (PF) and hepatotoxicity. This study aimed to investigate the influence of alpha lipoic acid (ALA) on AMD-induced PF and hepatotoxicity in male Wistar rats. AMD administration resulted in elevated lung contents of hydroxyproline (Hyp), malondialdehyde (MDA), and increased serum levels of transforming growth factor beta-1 (TGF-β1), interferon-γ (IFN-γ), alanine amino transaminase (ALT), aspartate amino transaminase (AST), total cholesterol (TC), and glucose. On the other side, lung content of glutathione reduced (GSH) and serum levels of total anti-oxidant capacity (TAC) were significantly decreased. Histopathologically, AMD caused PF, produced a mild hepatic injury, and increased expression of alpha smooth muscle actin (α-SMA). Treatment with ALA produced a significant reversal of the oxidative stress, fibrosis, and inflammation parameters with reductions in α-SMA expressions, leading to amelioration of histopathological lesions. ALA might provide supportive therapy in AMD-receiving cardiovascular patients.
... The liver is a vital organ that performs a wide range of functions, including biotransformation and detoxification of endogenous and exogenous harmful substances and metabolic homeostasis [45][46]. It has been reported that numerous drugs and chemicals cause liver injury, which is generally considered to be the main cause of chronic liver disease [47]. CCl 4 belongs to the hepatotoxin class which plays a role after the metabolic activation. ...
... Also, it increases the level of MMP-9, one of the MMPs which can play an important role in predicting and repairing the condition of liver injury and inflammation [58,61]. It has been observed that CCl 4 application indicated a quite significant increase in the AKT, MAPK STAT3, and TGF-b expression and that the Nrf2 expression, which is an important transcription factor that regulates the expression of a group of detoxifying and antioxidant defense genes in the liver, decreased significantly [47,70,71] (Table 1). CCl 4 causes upregulation of the proapoptotic protein Bax and downregulation of the antiapoptotic protein Bcl2. ...
Several chemicals, including environmental toxicants and clinically useful drugs, cause severe cellular damage to different organs of our body through metabolic activation to highly reactive substances such as free radicals. Carbon tetrachloride is an organic compound of which chemical formula is CCl₄. CCl4 is strong toxic in the kidney, testicle, brain, heart, lung, other tissues, and particularly in the liver. CCl4 is a powerful hepatoxic, nephrotoxic and prooxidant agent which is widely used to induce hepatotoxicity in experimental animals and to create hepatocellular carcinoma, hepatic fibrosis/cirrhosis and liver injury, chemical hepatitis model, renal failure model, and nephrotoxicity model in recent years. The damage-causing mechanism of CCl4 in tissues can be explained as oxidative damage caused by lipid peroxidation which starts after the conversion of CCl4 to free radicals of highly toxic trichloromethyl radicals (•CCl₃) and trichloromethyl peroxyl radical (•CCl₃O2) via cytochrome P450 enzyme. Complete disruption of lipids (i.e., peroxidation) is the hallmark of oxidative damage. Free radicals are structures that contain one or more unpaired electrons in atomic or molecular orbitals. These toxic free radicals induce a chain reaction and lipid peroxidation in membrane-like structures rich in phospholipids, such as mitochondria and endoplasmic reticulum. CCl4-induced lipid peroxidation is the cause of oxidative stress, mitochondrial stress, endoplasmic reticulum stress. Free radicals trigger many biological processes, such as apoptosis, necrosis, ferroptosis and autophagy. Recent researches state that the way to reduce or eliminate these CCl4-induced negative effects is the antioxidants originated from natural sources. For normal physiological function, there must be a balance between free radicals and antioxidants. If this balance is in favor of free radicals, various pathological conditions occur. Free radicals play a role in various pathological conditions including Pulmonary disease, ischemia / reperfusion rheumatological diseases, autoimmune disorders, cardiovascular diseases, cancer, kidney diseases, hypertension, eye diseases, neurological disorders, diabetes and aging. Free radicals are antagonized by antioxidants and quenched. Antioxidants do not only remove free radicals, but they also have anti-inflammatory, anti-allergic, antithrombotic, antiviral, and anti-carcinogenic activities. Antioxidants contain high phenol compounds and antioxidants have relatively low side effects compared to synthetic drugs. The antioxidants investigated in CCI4 toxicity are usually antioxidants from plants and are promising because of their rich resources and low side effects. Data were investigated using PubMed, EBSCO, Embase, Web of Science, DOAJ, Scopus and Google Scholar, Carbon tetrachloride, carbon tetrachloride-induced toxicity, oxidative stress, and free radical keywords. This study aims to enlighten the damage-causing mechanism created by free radicals which are produced by CCl4 on tissues/cells and to discuss the role of antioxidants in the prevention of tissue/cell damage. In the future, Antioxidants can be used as a therapeutic strategy to strengthen effective treatment against substances with high toxicity such as CCl4 and increase the antioxidant capacity of cells.
... The liver is a major organ in the metabolic clearance of the toxins, drugs, and other chemicals in vivo. A considerable number of medicines and chemicals have been reported to cause liver injury, which is generally accepted as a major cause of chronic liver diseases [1][2][3]. Chronic Liver diseases have become a major contributor to mortality in adults [4]. Liver fibrosis is a reversible pathological change in the progression of chronic hepatopathy to hepatic cirrhosis [5]. ...
Ethnopharmacological relevance:
The root of Averrhoa carambola L. (Oxalidaceae), a traditional Chinese medicine, was mainly used in ancient times in the treatment of urinary calculi, recurrent headache and joint pain.
Aim of the study:
Our aims were to explore the potential therapeutic effect of the extract of Averrhoa carambola L. (Oxalidaceae) roots (EACR) against hepatic fibrosis in CCl4-treated rats and to understand the underlying molecular mechanism.
Materials and methods:
Six groups of male Sprague Dawley rats were treated as follows: vehicle (olive oil), CCl4 alone, CCl4+colchicine, CCl4+EACR 1.0 g/kg, CCl4+EACR 0.5 g/kg and CCl4+EACR 0.25 g/kg. At the end of the 12th week, biomarkers of liver function, liver fibrosis, hepatic oxidative stress and antioxidant status were assayed, and histopathological and immunohistochemical evaluation of liver tissue were conducted to investigate the liver damage and fibrosis degree. Furthermore, expressions of COL-1a1, α-SMA, TGF-β1, Smad2, smad3, Smad4 and TIMP2 were examined by qPCR and/or western blot. The expressions of apoptosis-related proteins were also detected using western blot analysis.
Results:
EACR treatment markedly reduced the CCl4-induced elevation of serum aminotransferase activities, liver fibrosis indexes, and the extent of oxidative stress. EACR treatment also significantly reduced the accumulation of collagen and the immunostaining of α-SMA, TGF-β1 and Smad2, 4 and 7 in the liver of CCl4 treated rats. In addition, EACR treatment markedly reversed the CCl4-induced increase in mRNA expression of COL-1a1, α-SMA, TIMP2, TGF-β1, Smad2 and Smad4 and suppressed the expressions of α-SMA, TIMP2, TGF-β1, smad2, 3 and 4, BAX and cleaved caspase-3 proteins. Meanwhile, EACR treatment also significantly elevated the mRNA expression of Smad7 and the protein expression of Smad7 and Bcl-2.
Conclusion:
These results suggest that EACR has protective activity against liver fibrosis. The anti-fibrotic activity of EACR in vivo is associated with enhanced antioxidant, apoptosis-inhibition and increased MMP-2/TIMP-2 expression ratio, and with modulation of TGF-β1/Smad signaling pathway.
